For patients suffering from late phase non-small cell lung cancer (NSCLC), targeted therapies against epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations are standard treatment regimens today. However, the duration of efficacy of these drugs is generally very short, with resistance occurring within 9 to 11 months, due to the ability of cancer cells to evade the therapeutic activity of EGFR or ALK inhibitors by mutation and altered growth patterns. It has been reported that for Asian patients with late phase non-small cell lung cancer, 50% of the acquired resistance to anti-EGFR treatments is caused by T790M mutation.
In order to overcome the related drug resistance caused by T790M mutation, some irreversible ATP competitive inhibitors (such as HMPL-813, CI-1033, HKI-272, HS-10182) have entered the clinical research phase. The structure of the irreversible inhibitor contains a receptor fragment that may undergo Michael addition reaction, which is capable of generating a covalent bond with a thiol group (SH) in a conserved amino acid residue (Cys797) of the receptor binding site. The binding ability of such inhibitors to EGFR via irreversible covalent bonds is generally stronger than the binding ability of the reversible inhibitors to EGFR (see Journal of Medicinal Chemistry, 2009, 52:1231-1236). Nevertheless, the clinical trial results of the above irreversible inhibitors indicate that these inhibitors still have certain limitations, such as toxic effects due to off-target effects, and failure to achieve sufficient drug concentration in patients due to side effects caused by low selectivity. Therefore, the development of a new type of irreversible EGFR inhibitor has a great clinical significance and application prospect.
AZD9291, developed and marketed by AstraZeneca, is the first third-generation oral, irreversible, selective EGFR mutation inhibitor that may be used for both activated and resistant mutant EGFR, that is, AZD9291 may make the drug resistance caused by T790M mutation ineffective. AZD9291 has a relatively good therapeutic effect on NSCLC patients who have resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and have T7901M mutation. The structure of AZD9291 is disclosed in Chinese patent application CN103702990A, which also discloses the polymorph of AZD9291 and its pharmaceutically acceptable form mesylate salt.
Since the third generation EGFR inhibitor has unique efficacy and AZD9291 is the only product in the market, competition for new drugs is very fierce. Chinese patent application CN106132957A discloses a series of 2-arylamine pyridine, pyrimidine or triazine deriviatives, which were structurally characterized. In addition, this application also conducted activity tests for the above compounds at cellular level. The results show that these compounds have high EGFR inhibitory activity, while have relatively low inhibitory activity towards wild type EGFR, thus may be developed into novel anti-tumor drugs. However, the above application lacks research and protection of the pharmaceutically acceptable form (for example, a salt-based crystal form) of the crude drug, and needs further development and improvement.